It is well established that activation of GLUT4 translocation by insulin requires a PI3K signal involving the upstream IR and IRS activators and the downstream Akt and PKC target
enzymes and AS160 protein. Some studies over the past decade have also suggested that a
second pathway occurs as a consequence of Cbl tyrosine phosphorylation (57), (58). Cbl and
the adaptor protein CAP are recruited to the insulin receptor by APS (59). Once tyrosine
phosphorylated by the receptor, Cbl can recruit the adaptor protein CrkII to lipid rafts, along with the guanyl nucleotide exchange factor C3G (60). C3G can then activate the GTP-binding protein TC10, which resides in lipid rafts . The correct spatial compartmentalization of these signaling molecules in the lipid raft microdomain appears to be essential or insulinstimulated GLUT4 translocation and glucose transport, as these insulin-mediated events are abolished by dominant-interfering mutants of CAP that prevent the localization of Cbl to lipid rafts (61). Nevertheless, investigation suggests a role of TC10 in the regulation of actin dynamics and phosphoinositides. Cellular cortical actin exists in two forms: monomeric globular actin (G-actin) and filamentous actin (F-actin). In the case of cytosketal fusion, microtubules and cortical actin plays the important role. When the actin network (62) in skeletal muscle is treated with actin depolymerizing agent cytochalasin D or the actin monomer binding red sea sponge toxins Latrunculin A or B, it leads to the inhibition of glucose uptake and GLUT4 translocation (63). Two potentially overlapping models hypothesizing the role of actin in glucose uptake. According to the first one, insulin causes cortical actin remodeling, such that incoming vesicles can travel through the peripheral actin mesh to fuse with the plasma membrane (64) . The second suggests that actin filaments function as “highways,” upon which vesicles travel to reach the plasma membrane. Regardless of the exact actin function, it is apparent that insulin signaling to rearrange cortical actin represents a required pathway for optimal movement or fusion of GLUT4-containing vesicles and plasma membranes.

PI3K-independent signaling: It is well established that activation of GLUT4 translocation by insulin requires a PI3K signal involving the upstream IR and IRS activators and the downstream Akt and PKC target enzymes and AS160 protein as presented above (Fig.A). Some studies over the past decade have also suggested that a second pathway (Fig.B) occurs as a consequence of Cbl tyrosine phosphorylation59,60. Cbl and the adaptor protein CAP are recruited to the insulin receptor by APS61. Once tyrosine phosphorylated by the receptor, Cbl can recruit the adaptor protein CrkII to lipid rafts, along with the guanyl nucleotide exchange factor C3G62. C3G can then activate the GTP-binding protein TC10, which resides in lipid rafts63. The correct spatial compartmentalization of these signaling molecules in the lipid raft microdomain appears to be essential for insulin-stimulated GLUT4 translocation and glucose transport, as these insulin-mediated events are abolished by dominant-interfering mutants of CAP that prevent the localization of Cbl to lipid rafts64. [...]

Nevertheless, investigation suggests a role of TC10 in the regulation of actin dynamics69-74 and phosphoinositides75.

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Cortical actin: Cellular cortical actin exists in two forms: monomeric globular actin (G-actin) and filamentous actin (F-actin).[...] Disrupting the actin network in cultured cells or in intact rat skeletal muscle with the actin-depolymerizing agent cytochalasin D, or the actin monomer binding Red Sea Sponge toxins Latrunculin A or B, inhibits insulin-stimulated GLUT4 translocation and glucose uptake77,80,81. [...] Overall, these studies have given rise to two potentially overlapping models hypothesizing the role of actin in glucose uptake. The first proposes that insulin causes cortical actin remodeling, such that incoming vesicles can travel through the peripheral actin mesh to fuse with the plasma membrane. The second suggests that actin filaments function as “highways,” upon which vesicles travel to reach the plasma membrane71. Regardless of the exact actin function, it is apparent that insulin signaling to rearrange cortical actin represents a required pathway for optimal movement or fusion of GLUT4-containing vesicles and plasma membranes.